The present proposal represents a competitive renewal application. The proposed research focuses on the effects of age on the regulation of activity and functions of the cortical cholinergic afferent system. The research conducted during the previous funding period revealed new insights into the effects of age on the regulation of cortical acetylcholine (ACh) release and attentional abilities. In contrast to the rather limited effects of age per se on cortical ACh release and on attentional functions, our recent experiments on the effects of age in animals with an experimentally-induced partial decrease in the density of cortical cholinergic inputs. While the deafferentiation-induced decrease in baseline cortical ACh release did not differ between young and aged animals, and while stimulated cortical ACh release in young- deafferented animals was identical to that from young-sham-deafferented and aged/sham-deafferented animals, aged/deafferented animals exhibited a strongly attenuated increase in cortical ACh release in response to behavioral and neuropharmacological stimuli. These data suggest that age acted as an intervening variable in deafferented animals, resulting in an age-related attenuation of the capacity of residual cholinergic inputs to the cortex to respond to stimulation. The proposed research will test hypotheses about the neuronal mechanisms mediating the interactions between the effects of aging and partial deafferentation on ACh release, and about the significance of such interactions for the attentional abilities of aged rats. As age-related cognitive disorders may derive from interactions between the effects of age and pre-existing neuropathological processes, and as the decline in cortical cholinergic function remains a primary neuropathological candidate in the development of age-related cognitive disorders, this research will reveal important insights in the neuronal processes underlying the effects of age on the functions of a compromised cortical cholinergic input system.